scholarly journals Genetic landscape of recessive diseases in the Vietnamese population from large-scale clinical exome sequencing

2020 ◽  
Author(s):  
Ngoc Hieu Tran ◽  
Thanh-Huong Nguyen Thi ◽  
Hung-Sang Tang ◽  
Le-Phuc Hoang ◽  
Trung-Hieu Le Nguyen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Cost Effective ◽  
Carrier Screening ◽  
Beta Thalassemia ◽  
Genetic Studies ◽  
Screening Programs ◽  
Pathogenic Variants ◽  
Clinical Exome Sequencing ◽  
Vietnamese Population ◽  
Effective Carrier

AbstractPurposeAccurate profiling of population-specific recessive diseases is essential for the design of cost-effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still under-represented in existing genetic studies. Here we reported the first comprehensive study of recessive diseases in the Vietnamese population.MethodsClinical exome sequencing (CES) data of 4,503 disease-associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population.ResultsEighty-five recessive diseases were identified in the Vietnamese population, among which seventeen diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were especially prevalent in the Vietnamese population with carrier frequencies of 2-12 times higher than in other East Asia or the world populations, including Beta-thalassemia (1 in 25), citrin deficiency (1 in 33) and phenylketonuria (1 in 40). Seven novel pathogenic and three likely pathogenic variants associated with nine recessive diseases were also discovered.ConclusionsThe comprehensive profile of recessive diseases identified in this study shall enable the design of cost-effective carrier screening programs specific to the Vietnamese population. The newly discovered pathogenic variants may also exist in other populations at extremely low frequencies, thus representing a valuable resource for future research. Our study has demonstrated the advantage of population-specific genetic studies to advance the knowledge and practice of medical genetics.

scholarly journals PATHOGENIC VARIANTS WITHIN ACMG SECONDARY FINDINGS GENES IN 24,591 HEALTHY INDIVIDUALS USING CLINICAL EXOME SEQUENCING FOR CARRIER SCREENING

2020 ◽  
Vol 114 (3) ◽  
pp. e237
Author(s):  
Pere Mir Pardo ◽  
Joaquin Panadero ◽  
Gema Escribano ◽  
Jorge Jimenez-Almazán ◽  
Roberto Alonso ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Carrier Screening ◽  
Healthy Individuals ◽  
Secondary Findings ◽  
Pathogenic Variants ◽  
Clinical Exome Sequencing

scholarly journals Genetic landscape of recessive diseases in the Vietnamese population from large‐scale clinical exome sequencing

2021 ◽  
Author(s):  
Ngoc Hieu Tran ◽  
Thanh‐Huong Nguyen Thi ◽  
Hung‐Sang Tang ◽  
Le‐Phuc Hoang ◽  
Trung‐Hieu Le Nguyen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Large Scale ◽  
Clinical Exome Sequencing ◽  
Genetic Landscape ◽  
Vietnamese Population

Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

2016 ◽  
Vol 87 (2) ◽  
pp. 88-94 ◽  
Author(s):  
Nelmar Valentina Ortiz-Cabrera ◽  
Rosa Riveiro-Álvarez ◽  
Miguel Ángel López-Martínez ◽  
Pilar Pérez-Segura ◽  
Isabel Aragón-Gómez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Pathogenic Variants ◽  
Idiopathic Central Precocious Puberty ◽  
Clinical Exome Sequencing

scholarly journals Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ionut-Florin Iancu ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
Maria Jose Trujillo-Tiebas ◽  
Rosa Riveiro-Alvarez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Diseases ◽  
Molecular Diagnostic ◽  
Rule Based ◽  
Variants Of Uncertain Significance ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Clinical Exome Sequencing ◽  
Uncertain Significance

AbstractInherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N = 390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p = 4.07e-04). Significantly fewer VUS were reported in recessive cases (p = 2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p = 3.89e-04, p = 6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p = 6.73e-08 and p = 2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.

Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

2021 ◽  
pp. jmedgenet-2020-107317
Author(s):  
Tiana M Scott ◽  
Ian M Campbell ◽  
Andres Hernandez-Garcia ◽  
Seema R Lalani ◽  
Pengfei Liu ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Exome Sequencing ◽  
Diaphragmatic Hernia ◽  
De Novo ◽  
Diagnostic Yield ◽  
Fanconi Anaemia ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Clinical Exome Sequencing ◽  
Made In

BackgroundCongenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.MethodsWe analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.ResultsAmong the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports.ConclusionWe conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.

scholarly journals Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders

2021 ◽  
pp. jmedgenet-2020-107303
Author(s):  
Leslie Patricia Molina-Ramírez ◽  
Claire Kyle ◽  
Jamie M Ellingford ◽  
Ronnie Wright ◽  
Algy Taylor ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Gene Selection ◽  
Diagnostic Yield ◽  
Cost Effective ◽  
Gene Panel ◽  
Monogenic Disorders ◽  
Use Of Resources ◽  
Clinical Exome Sequencing ◽  
Cost Effective Approach ◽  
Gene Panels

PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.

scholarly journals Assessing utility of clinical exome sequencing in diagnosis of rare idiopathic neurodevelopmental disorders in Indian population

2019 ◽  
Author(s):  
Harsh Sheth ◽  
Dhairya Pancholi ◽  
Riddhi Bhavsar ◽  
Ashraf U. Mannan ◽  
Aparna Ganapathy ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
Indian Population ◽  
De Novo ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Cost Effective ◽  
European Population ◽  
Clinical Exome Sequencing ◽  
Deep Phenotyping

Abstract Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical exome sequencing (CES) has been shown to provide a high diagnostic yield for these disorders in the European population but remains to be demonstrated for the Indian population. Methods: A cohort of 19 idiopathic patients with neurological phenotypes, primarily intellectual disability and developmental delay, were recruited. CES covering 4620 genes was performed on all patients. Candidate variants were validated by Sanger sequencing. Results: CES in 19 patients provided identified 21 variants across 16 genes which have been associated with different neurological disorders. Fifteen variants were reported previously and 6 variants were novel to our study. Eleven patients were diagnosed with autosomal dominant de novo variants, 7 with autosomal recessive and 1 with X-linked recessive variants. CES provided definitive diagnosis to 10 patients, hence the diagnostic yield was 53%. Conclusion: Our study suggests that the diagnostic yield of CES in the Indian population is comparable to that reported in the European population. CES together with deep phenotyping could be a cost-effective way of diagnosing rare neurological disorders in the Indian population.

An audit and insights from clinical exome sequencing in psychiatry: genotype-phenotype correlation

2020 ◽  
Author(s):  
Jayant Mahadevan ◽  
Reeteka Sud ◽  
Ravi Kumar Nadella ◽  
Vani P ◽  
Anand G Subramaniam ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Psychiatric Symptoms ◽  
Pathogenic Variant ◽  
Clinical Exome Sequencing ◽  
Mapt Gene ◽  
Nf1 Gene ◽  
Novel Variant ◽  
History Of ◽  
Atypical Presentations ◽  
Minor Physical Anomalies

BACKGROUND:Psychiatric syndromes have polymorphic symptomatology, and are known to be heritable. Psychiatric symptoms (and even syndromes) often occur as part of the clinical presentation in rare Mendelian syndromes. Clinical exome sequencing reports may help with refining diagnosis and influence treatment decisions, in addition to providing a window into the biology of brain and behaviour. We describe a clinical audit of 12 individuals who sought treatment at our hospital, and for whom targeted sequencing was ordered. Three cases are discussed in detail to demonstrate correlations between genotype and phenotype in the clinic.METHODS:Targeted Next-Generation Sequencing (NGS) was done using Clinical Exome Panel (TruSight One, Illumina) covering coding exons and flanking intronic sequences of 4811 genes associated with known inherited diseases. Variants detected were classified according to the American College for Medical Genetics (ACMG) recommendation for standards of interpretation and reporting of sequence variations.RESULTS:Ten out of twelve cases had at least one pathogenic variant. In one of these cases, we detected a known pathogenic variant in MAPT gene in a suspected FTD case, which helped us to confirm the diagnosis. In another case, we detected a novel variant predicted to be deleterious in NF1 gene. Identification of this mutation suggested a change in treatment for the patient, that was of benefit. The same patient also harboured a novel variant in the TRIO gene. This gene may be involved in biological processes that underlie the patient’s psychiatric illness.CONCLUSIONS:The cases discussed here exemplify different scenarios under which targeted exome sequencing can find meaningful application in the clinic: confirming diagnosis (MAPT variant), or modifying treatment (NF1). We suggest that clinical exome sequencing can be a helpful addition to a clinician’s toolkit when there are expediting factors to consider— such as early-onset, strong family history of mental illness, complex/atypical presentations and minor physical anomalies or neurocutaneous markers.

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